- Email: [email protected]
Chronic diseases in developing countries
Comment
That the frequency of exacerbations was no different between genotype subgroups provides important reassurance about current treatment of the substantial proportion of patients whose asthma is quite easy to control using one or other of the treatment regimens tested in the Bleecker study. However, this reassurance does not completely clear the air about either the safety of long-acting agonists or the role of the ADRB2 genotype. Bleecker and colleagues’ study has important caveats. First, all patients were receiving inhaled corticosteroids which could have modified the effect of inflammatory mediators on ADRB2 function9 and hence protect the patient, albeit indirectly, from any adverse effects of β-agonist use. Second, total β-agonist exposure was limited not only because the dose of either formoterol or salmeterol was modest, but also because patients taking frequent doses of short-acting agents for symptom relief were specifically excluded. These caveats are important, because such conditions did not necessarily apply in the previous studies that highlighted adverse outcomes with β agonists.5,6,10 It remains a concern that, in patients with difficult-to-manage asthma, many of whom take β2 agonists to excess, treatment might itself contribute adversely rather than beneficially to their clinical status: increasing β-agonist use predisposes patients to increasing airway inflammation and vice versa.10 To date, this hypothesis has neither been definitively confirmed nor refuted; hence the ongoing controversy. There is no clear evidence that Arg-16 homozygotes are more likely to have difficult-to-treat asthma than are other ADRB2 genotypes. However, the observation that the persistence of asthma is more likely in Arg-16 homozygotes maintains the possibility of an interaction between β agonists and ADRB2
genotype.11 Bleecker and colleagues have addressed very relevant and important questions, but their study has not answered them all. Further data from prospective pharmacogenetic studies in the USA and Europe are awaited. With the development of newer ultra-long-acting β agonists for the treatment of asthma and chronic obstructive pulmonary disease, the safety profile of this class of drugs should continue to demand vigilance. *D Robin Taylor, Ian P Hall Dunedin School of Medicine, University of Otago, Dunedin, New Zealand (DRT); and Faculty of Medicine, University of Nottingham, Nottingham, UK (IPH) [email protected] We declare that we have no conflict of interest. 1
2
3
4 5 6
7
8
9 10 11
Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the β2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993; 8: 334–39. Israel E, Chinchilli VM, Ford JG, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004; 364: 1505–12. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term β agonist use: influence of β2 adrenoceptor polymorphism. Thorax 2000; 55: 762–67. O’Byrne PM, Adelroth E. β2 deja vu. Chest 2006; 129: 3–5. Wechsler ME, Lehman E, Lazarus SC. β-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006; 173: 519–26. Palmer CN, Lipworth BJ, Lee S, Ismail T, Macgregor DF, Mukhopadhyay S. Arginine-16 β2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 2006; 61: 940–44. Bleecker ER, Yancey SW, Baitinger LA, et al. Salmeterol response is not affected by β2-adrenergic receptor genotype in subjects with persistent asthma. J Allergy Clin Immunol 2006; 118: 809–16. Bleecker ER, Postma DS, Lawrence RM, Meyers DA, Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to long-acting β2-agonist therapy. Lancet 2007; 370: 2118–25. Shore SA. Cytokine regulation of beta-adrenergic responses in airway smooth muscle. J Allergy Clin Immunol 2002; 110 (suppl 6): S255–60. Sears MR, Taylor DR. The β2-agonist controversy: observations, explanations and relationship to asthma epidemiology. Drug Saf 1994; 11: 259–83. Hall IP, Blakey JD, Al Balushi KA, et al. β2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: a genetic association study. Lancet 2006; 368: 771–79.
Chronic diseases in developing countries See Series page 2152
2076
The idea that a practitioner in a low-income country who investigates a patient’s visual impairment might discover that diabetic retinopathy or glaucoma is the cause, not onchocerciasis, comes as a surprise to those who associate the health of developing countries solely with the major infectious diseases. The Lancet‘s Series in 20051 and the current one (which ends today)2 show that chronic disease is a feature in the health landscape
even of countries in the early stages of demographic and economic transition. The coexistence of a substantial burden of cancer, vascular disease, diabetes mellitus, and arthritis with HIV, tuberculosis, and malaria would challenge even the most mature and well-resourced health-care system. This situation is faced by many low-income and middle-income countries, as the analyses in the Lancet papers make clear. www.thelancet.com Vol 370 December 22/29, 2007
The latest Series identifies three costed models for delivering public-health interventions in 23 middleincome and low-income countries to reduce the impact of dying early from chronic diseases: two population strategies (reduction of tobacco use and salt intake) and a multidrug regimen (a statin, aspirin, and two blood-pressure-lowering drugs) that targets high-risk individuals.3,4 The Series also calls for a global Chronic Disease Goal to complement the Millennium Development Goals, along with actions for governments, multilateral organisations, industry, academia, and civil society, and a proposal for a new global-health partnership for chronic diseases to complement the analytical work.2,5 Prevention and treatment of chronic disease require strong and sustainable health systems.6 A new Millennium Development Goal or a new Global Health Partnership for chronic diseases is more likely to lead to more disease-specific programming than to the stronger health systems that are needed. The architecture of international health is already too complicated. The addition of yet another funding stream is almost certainly not required. Building advocacy for action through an enhanced Chronic Disease Action Group is a better way forward.7 Where do we go from here? For policymakers in the 23 countries that form part of the report (as well as other middle-income and developing countries), and those in high-income countries that work with them, there are several challenges. First, epidemiological research is needed to see whether the models3,4 will work in the real world: how effective these interventions are in targeting those in need, optimum delivery methods that include state and private health-care providers, and levels of adherence. The international community must now urgently work together to support the testing of these interventions in two or three small countries or regions of larger countries to clarify issues around cost, effectiveness, and the multidrug regimen and its safety. What, for example, is the safety of aspirin given to millions of people in developing countries? A second set of issues is specific to the multidrug regimen: more work is needed to make the four-drug combination available and affordable (Lim and colleagues4 currently estimate costs at US$13–87 per person a day). If further work shows that multidrug treatments are effective, they will need to benefit from flexibilities in Trade-Related Intellectual Property Rights (TRIPs),8 so www.thelancet.com Vol 370 December 22/29, 2007
WHO/Chris De Bode
Comment
Aravind Eye Hospital, Madurai, India
that poorer countries can access treatments for what is now a global public-health emergency.9 More fundamentally, it is important to absorb the lessons from high-income countries that are battling to combat the surge in problems such as obesity and alcohol-related illness. Targeting risk factors in prevention programmes is important, but relatively straightforward. The greatest need and the biggest difficulty is moving health from a sectoral activity to a broad-based multisectoral coalition of commitment at national or governmental and local levels.10 Up against this need, development agencies’ common mantra about strengthening health-care systems seems vague and narrow in scope. The opportunity is there if the development activity is focused not just on building health-care delivery systems but also on laying the foundations for a system that truly generates and sustains high levels of health. Governments, high, middle, or low income, all have to do better to place public health at the centre of their policymaking, and generate coherence in policies right 2077
Comment
across government that support the health of their nations. Additionally, the tackling of health inequalities and the social determinants of health is crucial to solving the problem of chronic diseases. How can governments and their partners do more to reduce the impact of chronic diseases in poor countries? First, more pressure from public-health advocates must be put on governments to ensure that their policies do not undermine the efforts of other governments to improve public health. For example, trade policy should not undermine the health of others—unfair trade policy is bad foreign policy. Second, governments and their partners must join up their research efforts for domestic and international-development, look for opportunities to share health services, and increase resources for chronicdisease research in developing and middle-income countries. The new UK Collaborative on Development Sciences is one vehicle to do this.11 Third, within the Organisation for Economic Co-operation and Development and other wealthy countries, more effective collaboration is needed between development ministries and ministries of health. The latter, with their wealth of experience in health systems and chronic-disease prevention and control, need to step up to this global-health challenge. Health ministries will need to work closely with and through bilateral and multilateral development agencies to ensure their actions are harmonised and do not complicate the existing architecture. For development-financing agencies, the lessons from the 2007 Lancet Series on chronic disease are clear. Ignoring chronic diseases is no longer an option. For ministers of finance from middle-income and lowincome countries there are equally clear messages.
They must urgently look to get more money into the sectors that can have an effect on chronic diseases. The provision of effective action to prevent chronic diseases and to slow their progression, and to maintain quality of life for people who have them, is complex and demanding. Innovative leadership, creativity, and sustained commitment are needed because evidence is scarce on methods to achieve effective change in the enormously diverse settings in which it is needed. *Nicholas Banatvala, Liam Donaldson Department of Health, London, SE1 8UG, UK [email protected] We declare that we have no conflict of interest. 1 2
3
4
5 6
7 8
9
10
11
Horton R. The neglected epidemic of chronic disease. Lancet 2005; 366: 1514. Beaglehole R, Ebrahim S, Reddy S, on behalf of the Chronic Disease Action Group. Prevention of chronic diseases: a call to action. Lancet 2007; 370: 2152–57. Asaria P, Chisholm D, Mathers C, Ezzati M, Beaglehole R. Chronic disease prevention: health effects and financial costs of strategies to reduce salt intake and control tobacco use. Lancet 2007; 370: 2044–53. Lim SS, Gaziano TA, Gakidou E, et al. Prevention of cardiovascular disease in high-risk individuals in low-income and middle-income countries: health effects and costs. Lancet 2007; 370: 2054–62. Nishtar S. Time for a global partnership on non-communicable diseases. Lancet 2007; 370: 1887–88. Fuster V, Voute J, Hunn M, Smith SC. Low priority of cardiovascular and chronic diseases on the global health agenda: a cause for concern. Circulation 2007; 116: 1966–70. The Lancet. Preventing chronic diseases: a forthcoming initiative. Lancet 2007; 370: 630. Bradford Kerry V, Lee K. TRIPS, the Doha declaration and paragraph 6 decision: what are the remaining steps for protecting access to medicines? Global Health 2007; 3: 3. Musungu SF, Villanueva S, Blasetti R. Utilising TRIPS flexibilities for public health protection through South-South Regional Frameworks. April, 2004. http://www.who.int/medicinedocs/collect/medicinedocs/pdf/s4968e/ s4968e.pdf (accessed Dec 13, 2007). World Health Organization. Preventing chronic diseases—a vital investment. 2005. http://www.who.int/chp/chronic_disease_report/en (accessed Dec 13, 2007). The UK Collaborative on Development Sciences. Welcome to UKCDS. http://www.ukcds.org.uk/index.php (accessed Dec 13, 2007).
International cooperation to combat chronic diseases See Series page 2152
2078
The epidemic of chronic diseases, which The Lancet’s Series1 on chronic diseases highlights, presents an urgent case for greater cooperation between nations, irrespective of their level of income. In view of the interdependence of health and prosperity and the increasing influences of globalisation, worldwide action is needed more than ever to improve health and thereby promote economic and social stability. The increased prevalence of chronic diseases and the increasing health inequalities they underpin are
made by human beings and are socially determined problems—hence solutions will be human and political. To avert the future consequences of this epidemic for governments and citizens, public-health professionals must catalyse political will to drive the systematic investment needed, engage with business, and empower people to co-create their own health and wellbeing.2 Although the urgency of tackling communicable diseases is clearly understood as a global issue, www.thelancet.com Vol 370 December 22/29, 2007
That the frequency of exacerbations was no different between genotype subgroups provides important reassurance about current treatment of the substantial proportion of patients whose asthma is quite easy to control using one or other of the treatment regimens tested in the Bleecker study. However, this reassurance does not completely clear the air about either the safety of long-acting agonists or the role of the ADRB2 genotype. Bleecker and colleagues’ study has important caveats. First, all patients were receiving inhaled corticosteroids which could have modified the effect of inflammatory mediators on ADRB2 function9 and hence protect the patient, albeit indirectly, from any adverse effects of β-agonist use. Second, total β-agonist exposure was limited not only because the dose of either formoterol or salmeterol was modest, but also because patients taking frequent doses of short-acting agents for symptom relief were specifically excluded. These caveats are important, because such conditions did not necessarily apply in the previous studies that highlighted adverse outcomes with β agonists.5,6,10 It remains a concern that, in patients with difficult-to-manage asthma, many of whom take β2 agonists to excess, treatment might itself contribute adversely rather than beneficially to their clinical status: increasing β-agonist use predisposes patients to increasing airway inflammation and vice versa.10 To date, this hypothesis has neither been definitively confirmed nor refuted; hence the ongoing controversy. There is no clear evidence that Arg-16 homozygotes are more likely to have difficult-to-treat asthma than are other ADRB2 genotypes. However, the observation that the persistence of asthma is more likely in Arg-16 homozygotes maintains the possibility of an interaction between β agonists and ADRB2
genotype.11 Bleecker and colleagues have addressed very relevant and important questions, but their study has not answered them all. Further data from prospective pharmacogenetic studies in the USA and Europe are awaited. With the development of newer ultra-long-acting β agonists for the treatment of asthma and chronic obstructive pulmonary disease, the safety profile of this class of drugs should continue to demand vigilance. *D Robin Taylor, Ian P Hall Dunedin School of Medicine, University of Otago, Dunedin, New Zealand (DRT); and Faculty of Medicine, University of Nottingham, Nottingham, UK (IPH) [email protected] We declare that we have no conflict of interest. 1
2
3
4 5 6
7
8
9 10 11
Reihsaus E, Innis M, MacIntyre N, Liggett SB. Mutations in the gene encoding for the β2-adrenergic receptor in normal and asthmatic subjects. Am J Respir Cell Mol Biol 1993; 8: 334–39. Israel E, Chinchilli VM, Ford JG, et al. Use of regularly scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 2004; 364: 1505–12. Taylor DR, Drazen JM, Herbison GP, Yandava CN, Hancox RJ, Town GI. Asthma exacerbations during long term β agonist use: influence of β2 adrenoceptor polymorphism. Thorax 2000; 55: 762–67. O’Byrne PM, Adelroth E. β2 deja vu. Chest 2006; 129: 3–5. Wechsler ME, Lehman E, Lazarus SC. β-adrenergic receptor polymorphisms and response to salmeterol. Am J Respir Crit Care Med 2006; 173: 519–26. Palmer CN, Lipworth BJ, Lee S, Ismail T, Macgregor DF, Mukhopadhyay S. Arginine-16 β2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol. Thorax 2006; 61: 940–44. Bleecker ER, Yancey SW, Baitinger LA, et al. Salmeterol response is not affected by β2-adrenergic receptor genotype in subjects with persistent asthma. J Allergy Clin Immunol 2006; 118: 809–16. Bleecker ER, Postma DS, Lawrence RM, Meyers DA, Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to long-acting β2-agonist therapy. Lancet 2007; 370: 2118–25. Shore SA. Cytokine regulation of beta-adrenergic responses in airway smooth muscle. J Allergy Clin Immunol 2002; 110 (suppl 6): S255–60. Sears MR, Taylor DR. The β2-agonist controversy: observations, explanations and relationship to asthma epidemiology. Drug Saf 1994; 11: 259–83. Hall IP, Blakey JD, Al Balushi KA, et al. β2-adrenoceptor polymorphisms and asthma from childhood to middle age in the British 1958 birth cohort: a genetic association study. Lancet 2006; 368: 771–79.
Chronic diseases in developing countries See Series page 2152
2076
The idea that a practitioner in a low-income country who investigates a patient’s visual impairment might discover that diabetic retinopathy or glaucoma is the cause, not onchocerciasis, comes as a surprise to those who associate the health of developing countries solely with the major infectious diseases. The Lancet‘s Series in 20051 and the current one (which ends today)2 show that chronic disease is a feature in the health landscape
even of countries in the early stages of demographic and economic transition. The coexistence of a substantial burden of cancer, vascular disease, diabetes mellitus, and arthritis with HIV, tuberculosis, and malaria would challenge even the most mature and well-resourced health-care system. This situation is faced by many low-income and middle-income countries, as the analyses in the Lancet papers make clear. www.thelancet.com Vol 370 December 22/29, 2007
The latest Series identifies three costed models for delivering public-health interventions in 23 middleincome and low-income countries to reduce the impact of dying early from chronic diseases: two population strategies (reduction of tobacco use and salt intake) and a multidrug regimen (a statin, aspirin, and two blood-pressure-lowering drugs) that targets high-risk individuals.3,4 The Series also calls for a global Chronic Disease Goal to complement the Millennium Development Goals, along with actions for governments, multilateral organisations, industry, academia, and civil society, and a proposal for a new global-health partnership for chronic diseases to complement the analytical work.2,5 Prevention and treatment of chronic disease require strong and sustainable health systems.6 A new Millennium Development Goal or a new Global Health Partnership for chronic diseases is more likely to lead to more disease-specific programming than to the stronger health systems that are needed. The architecture of international health is already too complicated. The addition of yet another funding stream is almost certainly not required. Building advocacy for action through an enhanced Chronic Disease Action Group is a better way forward.7 Where do we go from here? For policymakers in the 23 countries that form part of the report (as well as other middle-income and developing countries), and those in high-income countries that work with them, there are several challenges. First, epidemiological research is needed to see whether the models3,4 will work in the real world: how effective these interventions are in targeting those in need, optimum delivery methods that include state and private health-care providers, and levels of adherence. The international community must now urgently work together to support the testing of these interventions in two or three small countries or regions of larger countries to clarify issues around cost, effectiveness, and the multidrug regimen and its safety. What, for example, is the safety of aspirin given to millions of people in developing countries? A second set of issues is specific to the multidrug regimen: more work is needed to make the four-drug combination available and affordable (Lim and colleagues4 currently estimate costs at US$13–87 per person a day). If further work shows that multidrug treatments are effective, they will need to benefit from flexibilities in Trade-Related Intellectual Property Rights (TRIPs),8 so www.thelancet.com Vol 370 December 22/29, 2007
WHO/Chris De Bode
Comment
Aravind Eye Hospital, Madurai, India
that poorer countries can access treatments for what is now a global public-health emergency.9 More fundamentally, it is important to absorb the lessons from high-income countries that are battling to combat the surge in problems such as obesity and alcohol-related illness. Targeting risk factors in prevention programmes is important, but relatively straightforward. The greatest need and the biggest difficulty is moving health from a sectoral activity to a broad-based multisectoral coalition of commitment at national or governmental and local levels.10 Up against this need, development agencies’ common mantra about strengthening health-care systems seems vague and narrow in scope. The opportunity is there if the development activity is focused not just on building health-care delivery systems but also on laying the foundations for a system that truly generates and sustains high levels of health. Governments, high, middle, or low income, all have to do better to place public health at the centre of their policymaking, and generate coherence in policies right 2077
Comment
across government that support the health of their nations. Additionally, the tackling of health inequalities and the social determinants of health is crucial to solving the problem of chronic diseases. How can governments and their partners do more to reduce the impact of chronic diseases in poor countries? First, more pressure from public-health advocates must be put on governments to ensure that their policies do not undermine the efforts of other governments to improve public health. For example, trade policy should not undermine the health of others—unfair trade policy is bad foreign policy. Second, governments and their partners must join up their research efforts for domestic and international-development, look for opportunities to share health services, and increase resources for chronicdisease research in developing and middle-income countries. The new UK Collaborative on Development Sciences is one vehicle to do this.11 Third, within the Organisation for Economic Co-operation and Development and other wealthy countries, more effective collaboration is needed between development ministries and ministries of health. The latter, with their wealth of experience in health systems and chronic-disease prevention and control, need to step up to this global-health challenge. Health ministries will need to work closely with and through bilateral and multilateral development agencies to ensure their actions are harmonised and do not complicate the existing architecture. For development-financing agencies, the lessons from the 2007 Lancet Series on chronic disease are clear. Ignoring chronic diseases is no longer an option. For ministers of finance from middle-income and lowincome countries there are equally clear messages.
They must urgently look to get more money into the sectors that can have an effect on chronic diseases. The provision of effective action to prevent chronic diseases and to slow their progression, and to maintain quality of life for people who have them, is complex and demanding. Innovative leadership, creativity, and sustained commitment are needed because evidence is scarce on methods to achieve effective change in the enormously diverse settings in which it is needed. *Nicholas Banatvala, Liam Donaldson Department of Health, London, SE1 8UG, UK [email protected] We declare that we have no conflict of interest. 1 2
3
4
5 6
7 8
9
10
11
Horton R. The neglected epidemic of chronic disease. Lancet 2005; 366: 1514. Beaglehole R, Ebrahim S, Reddy S, on behalf of the Chronic Disease Action Group. Prevention of chronic diseases: a call to action. Lancet 2007; 370: 2152–57. Asaria P, Chisholm D, Mathers C, Ezzati M, Beaglehole R. Chronic disease prevention: health effects and financial costs of strategies to reduce salt intake and control tobacco use. Lancet 2007; 370: 2044–53. Lim SS, Gaziano TA, Gakidou E, et al. Prevention of cardiovascular disease in high-risk individuals in low-income and middle-income countries: health effects and costs. Lancet 2007; 370: 2054–62. Nishtar S. Time for a global partnership on non-communicable diseases. Lancet 2007; 370: 1887–88. Fuster V, Voute J, Hunn M, Smith SC. Low priority of cardiovascular and chronic diseases on the global health agenda: a cause for concern. Circulation 2007; 116: 1966–70. The Lancet. Preventing chronic diseases: a forthcoming initiative. Lancet 2007; 370: 630. Bradford Kerry V, Lee K. TRIPS, the Doha declaration and paragraph 6 decision: what are the remaining steps for protecting access to medicines? Global Health 2007; 3: 3. Musungu SF, Villanueva S, Blasetti R. Utilising TRIPS flexibilities for public health protection through South-South Regional Frameworks. April, 2004. http://www.who.int/medicinedocs/collect/medicinedocs/pdf/s4968e/ s4968e.pdf (accessed Dec 13, 2007). World Health Organization. Preventing chronic diseases—a vital investment. 2005. http://www.who.int/chp/chronic_disease_report/en (accessed Dec 13, 2007). The UK Collaborative on Development Sciences. Welcome to UKCDS. http://www.ukcds.org.uk/index.php (accessed Dec 13, 2007).
International cooperation to combat chronic diseases See Series page 2152
2078
The epidemic of chronic diseases, which The Lancet’s Series1 on chronic diseases highlights, presents an urgent case for greater cooperation between nations, irrespective of their level of income. In view of the interdependence of health and prosperity and the increasing influences of globalisation, worldwide action is needed more than ever to improve health and thereby promote economic and social stability. The increased prevalence of chronic diseases and the increasing health inequalities they underpin are
made by human beings and are socially determined problems—hence solutions will be human and political. To avert the future consequences of this epidemic for governments and citizens, public-health professionals must catalyse political will to drive the systematic investment needed, engage with business, and empower people to co-create their own health and wellbeing.2 Although the urgency of tackling communicable diseases is clearly understood as a global issue, www.thelancet.com Vol 370 December 22/29, 2007